Stable compositions containing N-propargyl-1-aminoindan

ABSTRACT

A pharmaceutical composition comprising as active ingredient a racemic, S(-), and R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof, and at least 60% by weight of at least one pentahydric or hexahydric alcohol. Optionally the composition may contain citric acid and magnesium stearate.

FIELD OF THE INVENTION

The present invention concerns formulations of racemic, S(-) or R(+)enantiomers of N-propargyl-1-aminoindan, and especially formulations ofthe enantiomer R(+) of N-propargyl-1-aminoindan (referred to hereinafteras R(+) PAI) which is a selective irreversible inhibitor of the B-formof the enzyme monoamine oxidase used, for example, for the treatment ofParkinson's disease. In the following the enzyme monoamine oxidase willbe referred to as MAO and the B-form thereof as MAO-B.

BACKGROUND OF THE INVENTION

GB 1 003 686 discloses a group of benzocycloalkane compounds in whichthe cycloalkane has from five to seven ring members and is substitutedby an N-(alkynylalkyl)amino group, and their use as MAO inhibitors. Thepatent further discloses the use of the subject compounds in admixturewith a variety of substances including various alcohols such as a benzylalcohol, stearyl alcohol, and methanol. The patent, however, does notteach how and by what criteria any of the many possible carriers andother ingredients are selected so as to overcome the stability problemof the product.

The object of the present invention is to provide stable formulationscomprising an effective amount of racemic, S(-) orR(+)-N-propargyl-1-aminoindan. For the sake of simplicity, theabbreviation PAI, unless specified otherwise, will be used to denote theenantiomers of N-propargyl-1-aminoindan, as well as their racemicmixtures.

SUMMARY OF THE INVENTION

In accordance with the invention it was surprisingly found that thestability of formulations comprising PAI can be significantly improvedby the incorporation of relatively large amounts of certain alcohols.

In accordance with the present invention there is provided apharmaceutical composition comprising as an active ingredient atherapeutically effective amount of a compound being a member selectedfrom the group of racemic, S(-), and R(+)-N-propargyl-1-aminoindan or apharmaceutically acceptable salt thereof, and at least 60% by weight ofat least one alcohol being a member selected from the group ofpentahydric and hexahydric alcohols.

In a preferred embodiment of the present invention the active ingredientis R(+)-N-propargyl-1-aminoindan.

Preferably the composition comprises at least 70% of said at least onealcohol.

Typically the alcohol used in accordance with of the invention, is amember selected from the group of mannitol, xylitol and sorbitol.

In accordance with the invention the PAI-comprising composition mayfurther include citric acid, preferably in an amount of 0.5 to 2% byweight.

If desired, compositions according to the invention may further comprisemagnesium stearate, preferably in an amount of 0.1 to 0.5% by weight.According to this embodiment, where the amount of said at least onealcohol is less than 70% by weight, the composition further comprisescitric acid in an amount specified above. Where the amount of said atleast one alcohol is at least 70% by weight, the inclusion of citricacid is optional.

The composition of the present invention may optionally also includeconventional additives such as fillers, lubricants, disintegrants,glidants, flavoring agents, sweeteners, coloring agents, and the like,all as known per se. Examples of fillers which may be used in accordancewith the present invention are lactose, starch, microcrystallinecellulose, maltrin and the like.

The compositions of the present invention may be prepared by methodsknown per se, familiar to those skilled in the art. For example, PAI andall other ingredients (with the exception of the lubricant, when used)may be screened and mixed thoroughly in a suitable granulating machine.The granulation may occur in the presence of purified water, followingwhich the composition is dried. The dry granulate may then be milled,lubricated and compressed into tablets. R(+) PAI itself may be prepared,for example, according to the process described in Example 6B ofW095/11016.

The following non-limiting examples are given by way of illustration.

EXAMPLES Example 1

    ______________________________________                                                               mg/tablet                                              ______________________________________                                        R(+)-N-propargyl-1-aminoindan mesylate                                                               3.12                                                   Mannitol               62.5                                                   Maltodextrin (Maltrin 150)                                                                           36.0                                                   Croscarmellose sodium (Ac-Di-Sol)                                                                    2.1                                                    Talc                   1.5                                                    ______________________________________                                    

Example 2

    ______________________________________                                                               mg/tablet                                              ______________________________________                                        R(+)-N-propargyl-1-aminoindan mesylate                                                               1.56                                                   Mannitol               79.14                                                  Starch                 10.0                                                   Pregelatinized starch  10.0                                                   Colloidal silicon dioxide                                                                            0.6                                                    Talc                   2.0                                                    Stearic acid           2.0                                                    ______________________________________                                    

Example 3

    ______________________________________                                                               mg/tablet                                              ______________________________________                                        R(+)-N-propargyl-1-aminoindan mesylate                                                               3.12                                                   Mannitol               76.58                                                  Starch                 10.0                                                   Pregelatinized starch  10.0                                                   Colloidal silicon dioxide                                                                            0.6                                                    Citric acid            1.0                                                    Talc                   2.0                                                    ______________________________________                                    

Example 4

    ______________________________________                                                               mg/tablet                                              ______________________________________                                        R(+)-N-propargyl-1-aminoindan mesylate                                                               3.12                                                   Mannitol               69.88                                                  Lactose (hydrous)      14.0                                                   Starch                 14.0                                                   Glyceryl Behenate (Compitrol 888 ATO)                                                                2.0                                                    ______________________________________                                    

Example 5

    ______________________________________                                                                 mg/tablet                                            ______________________________________                                        R(+)-N-propargyl-1-aminoindan mesylate                                                                 3.12                                                 Mannitol                 77.28                                                Starch                   10.0                                                 Starch STA-RX 1500       10.0                                                 Colloidal silicon dioxide, Aerosil                                                                     0.6                                                  Hydrogenated vegetable type I (Sterotex Dritex)                                                        2.0                                                  ______________________________________                                    

Example 6

In order to compare the compositions of the present invention with thoseknown in the prior art, two of the above formulations were compared witha formulation described in WO95/11016.

Formulation of WO95/11016 (Example 20)

    ______________________________________                                                             mg/tablet                                                ______________________________________                                        R(+)-N-propargyl-1-aminoindan HCl                                                                  1.56                                                     Lactose (hydrous)    50.0                                                     Pregelatinized starch                                                                              36.0                                                     Microcrystalline cellulose                                                                         14.0                                                     Sodium starch glycolate                                                                            2.14                                                     Talc                 1.0                                                      Magnesium stearate   0.5                                                      ______________________________________                                    

This formulation, as well as those described under Examples 2 and 3 ofthe present application were subjected to 6 months at 40° C. and 75%humidity. The percentage of degradants of the active material wasassayed at the end of the six month period.

The following procedure was adopted to determine the degradation of theformulations prepared. The tablets were finely powdered and extractedwith a diluent such as a mixture of water, acetonitrile and perchloricacid. An aliquot of the extraction product was injected into an HPLC andeluted using the same mixture as said diluent mixture. The areacorresponding to the PAI compound was determined as was that of anyother major peak. The calculations of degradation percent was made bycomparing the areas of the measured peaks with those obtained from thestandard preparation.

It was found that the formulation prepared according to the disclosureof Example 20 of W095/11016 contained after storage 3.08% degradantswhereas the formulations of Examples 2 and 3 contained 0.51% and lessthan 0.1% degradants, respectively.

Example 7

Formulations according to the present invention and others according tothe description given in Example 20 of WO95/11016 were preparedcontaining the ingredients shown in Table 1. The formulations describedin this Table are designated "PCT" when prepared in accordance with thedisclosure in WO95/11016, or by a number which corresponds to the numberof the Example in the present application, in which they are described.The qualifying symbols of A, B, C or D appearing next to some of thesedesignations denote certain variations in said formulations. Thepercentage of degradation, presented in Table 2, was calculated for allthe formulations of Table 1, after storing them for 1 month at 55° C. orfor 6 months at 40° C. and 75% humidity. Those formulations storedaccording to the latter storing conditions are marked in the Table withan astrix (*). As can be seen from Table 2, the stabilities of all thecompositions of the present invention was superior to those of the priorart.

    TABLE 1       - Example PCT PCT-A PCT-B PCT-C 1 1A 1B 1C 1D 2 2A 3 3A 4 5 5A 5B 5C 8     9       No. mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg       N-Proparg- 1.56 5.0 1.0 7.81 3.12 3.12 1.56 3.12 1.56 1.56 1.56 3.12     1.56 3.12 3.12 1.56 1.56 1.56 1.56 1.56       yl-       1(R)-Ami-       noindan       Mesylate       Mannitol     62.5 62.5    79.14 78.44 76.58 77.44 69.88 77.28 78.87     78.87 78.87       USP       Starch 36.0 47.0 36.0 47.0   36.0 36.0 36.0 10.0 10.0 10.0 10.0  10.0     10.0 10.0 10.0 10.0 10.0       STA-RX       1500       Starch NF          5.6 10.0 5.6 10.0 14.0 10.0 10.0 10.0 10.0 10.0     10.0       Starch NF          4.4  4.4       (in paste)       Colloidal          0.6 0.6 0.6 0.6  0.6 0.6 0.6 0.6 0.6 0.6       Silicon       Dioxide       (Aerosil       200)       Citric acid        1.0 2.0   1.0 1.0       Talc USP 1.0 1.5 1.0 1.5 1.5 1.5 1.0 1.0 1.0 2.0 2.0 2.0 2.0   2.0 2.0       2.0 2.0 2.0       Microcrys- 14.0 20.0 14.0 20.0   14.0 14.0 14.0       talline       Cellulose       (Avicel       102)       Stearic acid       2.0   2.0 2.0 2.0 2.0   2.0  2.0 2.0 2.0       NF       Lactose NF 50.0 66.0 50.0 66.0   50.0 47.44 46.44     14.0       Hydrous       Sodium 2.14 3.0 2.2 2.99   2.14 2.14 2.14       Starch       Glycolate       Magnesium 0.5 0.7 0.5 0.7  0.52 0.1 0.5 0.5       0.1 0.5 0.5       Stearate       AC-DI-SOL     2.1 2.1       Lactose       spray dried       Compritol       888 ATO       Maltrin     36.0 36.0        2.0       Sorbitol                   78.84       Xilitato 300                    78.84       Sterotex -               2.0       Dritex       Total 105.2 143.2 104.7 146.0 105.22 105.74 106.8 105.2 105.2 105.3     104.6 105.3 104.6 103.0 103.0 105.13 103.53 105.53 105.0 105.0       Weight (mg)

                                      TABLE 2                                     __________________________________________________________________________                                    Magneisum stearate                                                                      Example No: % Degradants                                                     Mannitol (%) Sorbitol (%)                                                     Xylitol (%) (%) Citric acid          __________________________________________________________________________                                             (%)                                  PCT(*)                                                                              2.26   --                 0.5      --                                     PCT-A 2.76 --   0.49 --                                                       PCT-B 1.46 --   0.49                                                          PCT-C(*) 2.59 --   0.5  --                                                    1 1.22 59.4   -- --                                                           1A 3.97 59.1   0.49 --                                                        1B 2.04 --   0.1  --                                                          1C 1.04 --   0.47 0.95                                                        1D 0.40 --   0.47 1.9                                                         2 0.29 75.1   -- --                                                           2A 0.27 75                                                                    3 0.02 72.7   -- 0.95                                                         3A 0.02 74      0.95                                                          4 0.02 67.8   -- --                                                           5 0.21 75     -- --                                                           5A 0.32 75     0.1  --                                                        5B 0.65 76.2   0.47 --                                                        5C 0.52 74.7   0.47 --                                                        6 0.74  75.1  -- --                                                           7 1.01   75.1 -- --                                                         __________________________________________________________________________

What is claimed is:
 1. A pharmaceutical composition in tablet formcomprising as an active ingredient a therapeutically effective amount ofR(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable saltthereof, and at least one alcohol selected from the group consisting ofpentahydric and hexahydric alcohols.
 2. The pharmaceutical compositionof claim 1, wherein said at least one alcohol comprises at least 60% byweight of the total composition.
 3. The pharmaceutical composition ofclaim 1, wherein the alcohol is selected from the group consisting ofmannitol, xylitol and sorbitol.
 4. The pharmaceutical composition ofclaim 1, further comprising citric acid.
 5. The pharmaceuticalcomposition of claim 4, wherein the amount of citric acid is 0.5 to 2%by weight of the total composition.
 6. The pharmaceutical composition ofclaim 1, further comprising magnesium stearate.
 7. The pharmaceuticalcomposition of claim 5, wherein the amount of magnesium stearate is 0.1to 0.5% by weight of the total composition.
 8. The pharmaceuticalcomposition of claim 1, in which the amount of said at least one alcoholis between 60% and 70% of the total composition, and further comprisingcitric acid.
 9. The pharmaceutical composition of claim 1, wherein saidactive ingredient is R(+)-N-propargyl-1-aminoindan.
 10. A pharmaceuticalcomposition in tablet form comprising as an active ingredient atherapeutically effective amount of R(+)-N-propargyl-1-aminoindan or apharmaceutically acceptable salt thereof, and at least 75% by weight ofat least one alcohol selected from the group consisting of mannitol,xylitol and sorbitol.
 11. The pharmaceutical composition of claim 10,wherein the amount of R(+)-N-propargyl-1-aminoindan or apharmaceutically acceptable salt thereof is 3.0% or less by weight ofthe composition, and wherein the alcohol at least 75% by weight of thecomposition.
 12. The pharmaceutical composition of claims, wherein thealcohol is mannitol.
 13. A pharmaceutical composition comprising as anactive ingredient a therapeutically effective amount of R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof,and at least one alcohol selected from the group consisting ofpentahydric and hexahydric alcohols.
 14. The pharmaceutical compositionof claim 13, wherein said at least one alcohol comprises at least 60% byweight of the total composition.
 15. The pharmaceutical composition ofclaim 13, wherein, the alcohol is selected from the group consisting ofmannitol, xylitol and sorbitol.
 16. The pharmaceutical composition ofclaim 13, further comprising citric acid.
 17. The pharmaceuticalcomposition of claim 16, wherein the amount of citric acid is 0.5 to 2%by weight of the total composition.
 18. The pharmaceutical compositionof claim 13, further comprising magnesium stearate.
 19. Thepharmaceutical composition of claim 18, wherein the amount of magnesiumstearate is 0.1 to 0.5% by weight of the total composition.
 20. Thepharmaceutical composition of claim 13, in which the amount of said atleast one alcohol is between 60% and 70% of the total composition, andfurther comprising citric acid.
 21. The pharmaceutical composition ofclaim 13, wherein said active ingredient isR(+)-N-propargyl-1-aminoindan.
 22. A pharmaceutical compositioncomprising as an active ingredient a therapeutically effective amount ofR(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable saltthereof, and at least 75% by weight of at least one alcohol selectedfrom the group consisting of mannitol, xylitol and sorbitol.
 23. Thepharmaceutical composition of claim 22, wherein the amount ofR(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable saltthereof is 3.0% or less by weight of the composition, and wherein thealcohol at least 75% by weight of the composition.
 24. Thepharmaceutical composition of claim 23, wherein the alcohol is mannitol.25. The pharmaceutical composition of claim 2, wherein the amount ofR(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable saltthereof is 3.0% or less by weight of the composition.
 26. Thepharmaceutical composition of claim 14, wherein the amount ofR(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable saltthereof is 3.0% or less by weight of the composition.